Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus
Identifieur interne : 001257 ( Pmc/Checkpoint ); précédent : 001256; suivant : 001258Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus
Auteurs : Jasper F. W. Chan [République populaire de Chine] ; Kwok-Hung Chan [République populaire de Chine] ; Richard Y. T. Kao [République populaire de Chine] ; Kelvin K. W. To [République populaire de Chine] ; Bo-Jian Zheng [République populaire de Chine] ; Clara P. Y. Li [République populaire de Chine] ; Patrick T. W. Li [République populaire de Chine] ; Jun Dai [République populaire de Chine] ; Florence K. Y. Mok [République populaire de Chine] ; Honglin Chen [République populaire de Chine] ; Frederick G. Hayden [États-Unis] ; Kwok-Yung Yuen [République populaire de Chine]Source :
- The Journal of Infection [ 0163-4453 ] ; 2013.
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged to cause fatal infections in patients in the Middle East and traveler-associated secondary cases in Europe and Africa. Person-to-person transmission is evident in outbreaks involving household and hospital contacts. Effective antivirals are urgently needed.
We used small compound-based forward chemical genetics to screen a chemical library of 1280 known drugs against influenza A virus in Biosafety Level-2 laboratory. We then assessed the anti-MERS-CoV activities of the identified compounds and of interferons, nelfinavir, and lopinavir because of their reported anti-coronavirus activities in terms of cytopathic effect inhibition, viral yield reduction, and plaque reduction assays in Biosafety Level-3 laboratory.
Ten compounds were identified as primary hits in high-throughput screening. Only mycophenolic acid exhibited low EC50 and high selectivity index. Additionally, ribavirin and interferons also exhibited
Interferon-β1b with mycophenolic acid should be considered in treatment trials of MERS.
Url:
DOI: 10.1016/j.jinf.2013.09.029
PubMed: 24096239
PubMed Central: 7112612
Affiliations:
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus</title>
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<author><name sortKey="Mok, Florence K Y" sort="Mok, Florence K Y" uniqKey="Mok F" first="Florence K. Y." last="Mok">Florence K. Y. Mok</name>
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<wicri:regionArea>Department of Microbiology, The University of Hong Kong, Hong Kong</wicri:regionArea>
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<author><name sortKey="Chen, Honglin" sort="Chen, Honglin" uniqKey="Chen H" first="Honglin" last="Chen">Honglin Chen</name>
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<wicri:regionArea>State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="aff2">Department of Microbiology, The University of Hong Kong, Hong Kong, China</nlm:aff>
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<wicri:regionArea>Department of Microbiology, The University of Hong Kong, Hong Kong</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="aff3">Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong</wicri:regionArea>
<wicri:noRegion>Hong Kong</wicri:noRegion>
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<author><name sortKey="Hayden, Frederick G" sort="Hayden, Frederick G" uniqKey="Hayden F" first="Frederick G." last="Hayden">Frederick G. Hayden</name>
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<wicri:regionArea>Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA</wicri:regionArea>
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<author><name sortKey="Yuen, Kwok Yung" sort="Yuen, Kwok Yung" uniqKey="Yuen K" first="Kwok-Yung" last="Yuen">Kwok-Yung Yuen</name>
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</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff2">Department of Microbiology, The University of Hong Kong, Hong Kong, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Department of Microbiology, The University of Hong Kong, Hong Kong</wicri:regionArea>
<wicri:noRegion>Hong Kong</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff3">Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong</wicri:regionArea>
<wicri:noRegion>Hong Kong</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">The Journal of Infection</title>
<idno type="ISSN">0163-4453</idno>
<idno type="eISSN">1532-2742</idno>
<imprint><date when="2013">2013</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><title>Summary</title>
<sec><title>Objectives</title>
<p>Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged to cause fatal infections in patients in the Middle East and traveler-associated secondary cases in Europe and Africa. Person-to-person transmission is evident in outbreaks involving household and hospital contacts. Effective antivirals are urgently needed.</p>
</sec>
<sec><title>Methods</title>
<p>We used small compound-based forward chemical genetics to screen a chemical library of 1280 known drugs against influenza A virus in Biosafety Level-2 laboratory. We then assessed the anti-MERS-CoV activities of the identified compounds and of interferons, nelfinavir, and lopinavir because of their reported anti-coronavirus activities in terms of cytopathic effect inhibition, viral yield reduction, and plaque reduction assays in Biosafety Level-3 laboratory.</p>
</sec>
<sec><title>Results</title>
<p>Ten compounds were identified as primary hits in high-throughput screening. Only mycophenolic acid exhibited low EC<sub>50</sub>
and high selectivity index. Additionally, ribavirin and interferons also exhibited <italic>in-vitro</italic>
anti-MERS-CoV activity. The serum concentrations achievable at therapeutic doses of mycophenolic acid and interferon-β1b were 60–300 and 3–4 times higher than the concentrations at which <italic>in-vitro</italic>
anti-MERS-CoV activities were demonstrated, whereas that of ribavirin was ∼2 times lower. Combination of mycophenolic acid and interferon-β1b lowered the EC<sub>50</sub>
of each drug by 1–3 times.</p>
</sec>
<sec><title>Conclusions</title>
<p>Interferon-β1b with mycophenolic acid should be considered in treatment trials of MERS.</p>
</sec>
</div>
</front>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Infect</journal-id>
<journal-id journal-id-type="iso-abbrev">J. Infect</journal-id>
<journal-title-group><journal-title>The Journal of Infection</journal-title>
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<issn pub-type="epub">1532-2742</issn>
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<article-id pub-id-type="pmc">7112612</article-id>
<article-id pub-id-type="publisher-id">S0163-4453(13)00298-3</article-id>
<article-id pub-id-type="doi">10.1016/j.jinf.2013.09.029</article-id>
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<xref rid="aff2" ref-type="aff">b</xref>
</contrib>
<contrib contrib-type="author" id="au9"><name><surname>Mok</surname>
<given-names>Florence K.Y.</given-names>
</name>
<xref rid="aff2" ref-type="aff">b</xref>
</contrib>
<contrib contrib-type="author" id="au10"><name><surname>Chen</surname>
<given-names>Honglin</given-names>
</name>
<xref rid="aff1" ref-type="aff">a</xref>
<xref rid="aff2" ref-type="aff">b</xref>
<xref rid="aff3" ref-type="aff">c</xref>
</contrib>
<contrib contrib-type="author" id="au11"><name><surname>Hayden</surname>
<given-names>Frederick G.</given-names>
</name>
<xref rid="aff4" ref-type="aff">d</xref>
</contrib>
<contrib contrib-type="author" id="au12"><name><surname>Yuen</surname>
<given-names>Kwok-Yung</given-names>
</name>
<email>kyyuen@hkucc.hku.hk</email>
<xref rid="aff1" ref-type="aff">a</xref>
<xref rid="aff2" ref-type="aff">b</xref>
<xref rid="aff3" ref-type="aff">c</xref>
<xref rid="cor1" ref-type="corresp">∗</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>a</label>
State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China</aff>
<aff id="aff2"><label>b</label>
Department of Microbiology, The University of Hong Kong, Hong Kong, China</aff>
<aff id="aff3"><label>c</label>
Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China</aff>
<aff id="aff4"><label>d</label>
Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA</aff>
<author-notes><corresp id="cor1"><label>∗</label>
Corresponding author. Carol Yu Centre for Infection, Department of Microbiology, The University of Hong Kong, Queen Mary Hospital, 102, Pokfulam Road, Pokfulam, Hong Kong, China. Tel.: +852 22554892; fax: +852 28551241. <email>kyyuen@hkucc.hku.hk</email>
</corresp>
<fn id="fn1"><label>e</label>
<p id="ntpara0010">The authors contributed equally to the manuscript.</p>
</fn>
</author-notes>
<pub-date pub-type="pmc-release"><day>3</day>
<month>10</month>
<year>2013</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub"><month>12</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="epub"><day>3</day>
<month>10</month>
<year>2013</year>
</pub-date>
<volume>67</volume>
<issue>6</issue>
<fpage>606</fpage>
<lpage>616</lpage>
<history><date date-type="accepted"><day>27</day>
<month>9</month>
<year>2013</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved.</copyright-statement>
<copyright-year>2013</copyright-year>
<copyright-holder>The British Infection Association</copyright-holder>
<license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p>
</license>
</permissions>
<abstract id="abs0010"><title>Summary</title>
<sec><title>Objectives</title>
<p>Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged to cause fatal infections in patients in the Middle East and traveler-associated secondary cases in Europe and Africa. Person-to-person transmission is evident in outbreaks involving household and hospital contacts. Effective antivirals are urgently needed.</p>
</sec>
<sec><title>Methods</title>
<p>We used small compound-based forward chemical genetics to screen a chemical library of 1280 known drugs against influenza A virus in Biosafety Level-2 laboratory. We then assessed the anti-MERS-CoV activities of the identified compounds and of interferons, nelfinavir, and lopinavir because of their reported anti-coronavirus activities in terms of cytopathic effect inhibition, viral yield reduction, and plaque reduction assays in Biosafety Level-3 laboratory.</p>
</sec>
<sec><title>Results</title>
<p>Ten compounds were identified as primary hits in high-throughput screening. Only mycophenolic acid exhibited low EC<sub>50</sub>
and high selectivity index. Additionally, ribavirin and interferons also exhibited <italic>in-vitro</italic>
anti-MERS-CoV activity. The serum concentrations achievable at therapeutic doses of mycophenolic acid and interferon-β1b were 60–300 and 3–4 times higher than the concentrations at which <italic>in-vitro</italic>
anti-MERS-CoV activities were demonstrated, whereas that of ribavirin was ∼2 times lower. Combination of mycophenolic acid and interferon-β1b lowered the EC<sub>50</sub>
of each drug by 1–3 times.</p>
</sec>
<sec><title>Conclusions</title>
<p>Interferon-β1b with mycophenolic acid should be considered in treatment trials of MERS.</p>
</sec>
</abstract>
<kwd-group id="kwrds0010"><title>Keywords</title>
<kwd>Coronavirus</kwd>
<kwd>Middle East</kwd>
<kwd>Mycophenolic acid</kwd>
<kwd>Interferon</kwd>
<kwd>Ribavirin</kwd>
<kwd>Antiviral</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>République populaire de Chine</li>
<li>États-Unis</li>
</country>
<region><li>Virginie</li>
</region>
</list>
<tree><country name="République populaire de Chine"><noRegion><name sortKey="Chan, Jasper F W" sort="Chan, Jasper F W" uniqKey="Chan J" first="Jasper F. W." last="Chan">Jasper F. W. Chan</name>
</noRegion>
<name sortKey="Chan, Jasper F W" sort="Chan, Jasper F W" uniqKey="Chan J" first="Jasper F. W." last="Chan">Jasper F. W. Chan</name>
<name sortKey="Chan, Jasper F W" sort="Chan, Jasper F W" uniqKey="Chan J" first="Jasper F. W." last="Chan">Jasper F. W. Chan</name>
<name sortKey="Chan, Kwok Hung" sort="Chan, Kwok Hung" uniqKey="Chan K" first="Kwok-Hung" last="Chan">Kwok-Hung Chan</name>
<name sortKey="Chen, Honglin" sort="Chen, Honglin" uniqKey="Chen H" first="Honglin" last="Chen">Honglin Chen</name>
<name sortKey="Chen, Honglin" sort="Chen, Honglin" uniqKey="Chen H" first="Honglin" last="Chen">Honglin Chen</name>
<name sortKey="Chen, Honglin" sort="Chen, Honglin" uniqKey="Chen H" first="Honglin" last="Chen">Honglin Chen</name>
<name sortKey="Dai, Jun" sort="Dai, Jun" uniqKey="Dai J" first="Jun" last="Dai">Jun Dai</name>
<name sortKey="Kao, Richard Y T" sort="Kao, Richard Y T" uniqKey="Kao R" first="Richard Y. T." last="Kao">Richard Y. T. Kao</name>
<name sortKey="Kao, Richard Y T" sort="Kao, Richard Y T" uniqKey="Kao R" first="Richard Y. T." last="Kao">Richard Y. T. Kao</name>
<name sortKey="Kao, Richard Y T" sort="Kao, Richard Y T" uniqKey="Kao R" first="Richard Y. T." last="Kao">Richard Y. T. Kao</name>
<name sortKey="Li, Clara P Y" sort="Li, Clara P Y" uniqKey="Li C" first="Clara P. Y." last="Li">Clara P. Y. Li</name>
<name sortKey="Li, Patrick T W" sort="Li, Patrick T W" uniqKey="Li P" first="Patrick T. W." last="Li">Patrick T. W. Li</name>
<name sortKey="Mok, Florence K Y" sort="Mok, Florence K Y" uniqKey="Mok F" first="Florence K. Y." last="Mok">Florence K. Y. Mok</name>
<name sortKey="To, Kelvin K W" sort="To, Kelvin K W" uniqKey="To K" first="Kelvin K. W." last="To">Kelvin K. W. To</name>
<name sortKey="To, Kelvin K W" sort="To, Kelvin K W" uniqKey="To K" first="Kelvin K. W." last="To">Kelvin K. W. To</name>
<name sortKey="To, Kelvin K W" sort="To, Kelvin K W" uniqKey="To K" first="Kelvin K. W." last="To">Kelvin K. W. To</name>
<name sortKey="Yuen, Kwok Yung" sort="Yuen, Kwok Yung" uniqKey="Yuen K" first="Kwok-Yung" last="Yuen">Kwok-Yung Yuen</name>
<name sortKey="Yuen, Kwok Yung" sort="Yuen, Kwok Yung" uniqKey="Yuen K" first="Kwok-Yung" last="Yuen">Kwok-Yung Yuen</name>
<name sortKey="Yuen, Kwok Yung" sort="Yuen, Kwok Yung" uniqKey="Yuen K" first="Kwok-Yung" last="Yuen">Kwok-Yung Yuen</name>
<name sortKey="Zheng, Bo Jian" sort="Zheng, Bo Jian" uniqKey="Zheng B" first="Bo-Jian" last="Zheng">Bo-Jian Zheng</name>
<name sortKey="Zheng, Bo Jian" sort="Zheng, Bo Jian" uniqKey="Zheng B" first="Bo-Jian" last="Zheng">Bo-Jian Zheng</name>
<name sortKey="Zheng, Bo Jian" sort="Zheng, Bo Jian" uniqKey="Zheng B" first="Bo-Jian" last="Zheng">Bo-Jian Zheng</name>
</country>
<country name="États-Unis"><region name="Virginie"><name sortKey="Hayden, Frederick G" sort="Hayden, Frederick G" uniqKey="Hayden F" first="Frederick G." last="Hayden">Frederick G. Hayden</name>
</region>
</country>
</tree>
</affiliations>
</record>
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